title: A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury.
abstract: Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3 mg to 9 mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3 mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.
authors.affiliation: Department of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. michael.fehlings@uhn.on.ca
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.forename: Nicholas
authors.initials: N
authors.lastname: Theodore
authors.forename: James
authors.initials: J
authors.lastname: Harrop
authors.forename: Gilles
authors.initials: G
authors.lastname: Maurais
authors.forename: Charles
authors.initials: C
authors.lastname: Kuntz
authors.forename: Chris I
authors.initials: CI
authors.lastname: Shaffrey
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kwon
authors.forename: Jens
authors.initials: J
authors.lastname: Chapman
authors.forename: Albert
authors.initials: A
authors.lastname: Yee
authors.forename: Allyson
authors.initials: A
authors.lastname: Tighe
authors.forename: Lisa
authors.initials: L
authors.lastname: McKerracher
mesh_terms: D036002:ADP Ribose Transferases / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D001905:Botulinum Toxins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D054460:rho-Associated Kinases; D001905:Botulinum Toxins